ABSTRACT Antiretroviral therapy (ART) can suppress HIV RNA and improve survival but concerns about the neurotoxicityofARTdrugshaveariseninrecentyearswiththepublicationofreportsofa)invitroevidenceof neuronal injury and b) neuropsychiatric adverse events (NP-AEs) of efavirenz, dolutegravir (DTG), and other drugs.AkeygapinourunderstandingoftheefficacyandsafetyofARTdrugsintheCNSisthepharmacology ofthesedrugsinthebrain.PublishedhumanstudieshavereportedthatconcentrationsofmostARTdrugsare substantiallylowerincerebrospinalfluid(CSF)thaninbloodbutrecentanimalstudieshavereportedthatART drug concentrations in the brain are substantially higher than expected by on CSF data. High ART drug concentrationsinthebraincouldbeacriticaldeterminantofneurotoxicityrisk.Tobetterunderstandtheinfluence ofARTdrugconcentrationsonNP-AEs,anewmethodisneededtomeasuretheseconcentrationsinthebrain oflivinghumans.ThisR21applicationproposeshighlyinnovativeresearchtodevelopsuchamethod,fluorine magnetic resonance spectroscopy (19F-MRS). This method can measure low concentration compounds, like fluorinateddrugs,thatfallwithinthe19F-MRSspectrainvivo.Thiscouldbehighlyvaluablesincemanycommonly used ART drugs, such as DTG and emtricitabine (FTC), are fluorinated. This method does not require administrationofaradioligandandhassuccessfullymeasuredconcentrationsoffluorinatedselectiveserotonin reuptakeinhibitorsinthepast.TheproposedresearchrespondswelltoRFA-MH-20-115andisorganizedinto 3aims:1)Developthe19F-MRSmethodtomeasureconcentrationsofDTGandFTCinthebrain,2)Measure DTG and FTC by 19F-MRS in 20 participants of the CHARTER Aging project (R01 MH107345), which will leverage NIMH?s investment in this cohort, and 3) Determine the relationships between DTG and FTC concentrations in brain tissue and assessments of neurocognitive performance, mood, sleep, and daily functioning,whicharebeingperformedbytheCHARTERAgingproject.Whiletheproposedsamplesizeissmall, the findings will provide proof-of-principle and preliminary data in support of future projects. The successful projectwilldevelopanewandhighlyimpactfultoolforresearchonARTneuropharmacologyandneurotoxicity and will lead to new, larger research projects. It may also be useful in development of new ART drugs. This methodcanalsobeusedtomeasureARTdrugsconcentrationsintissuesotherthanbrain(e.g.,lymphnodes) soitsdevelopmentcouldalsoleadtonewresearchonHIVpersistenceanderadication.